Synthesis of cyclopent-2-enones from furans using a nebulizer-based continuous flow photoreactor

A series of hydroxycyclopent-2-enones and methoxycyclopent-2-enones have been synthesized in a single operation from simple furan substrates using an innovative continuous flow nebulizer system (NebPhotOX). Photooxygenation of the furan substrates takes place in an aerosol within the NebPhotOX system.

SAFETY CAUTION: Measures were taken to eliminate all possible ignition sources from the fumehood area (sparks or flames, e.g. the electricity transformer for the LEDs was kept outside of the fumehood) in which the NebPhotOX system was operated.This included operating the reactor at room temperature and pressure conditions without any significant heat input from the low power LEDs used.In addition, the fumehood was always adequately ventilated with a high air flow.System operating conditions prevented oxygen stagnation in the system.Additional cautions included that the operator wears safety glasses with side shields and flame resistant safety clothing.For the fast reduction of the initially formed hydroperoxides of type A and B (Scheme 1), the two cooled collection flasks placed in series were prefilled with excess of Me 2 S in MeOH (3 equiv in the first flask and 1 equiv in the second flask).Even higher excesses of the reducing agent can be used.

Part B: Experimental procedures
Known compounds.The following compounds were prepared as previously reported: 1a, 1 1b, 2 1f.

General procedure for the preparation of 4-hydroxy-cyclopent-2-enones of type 2
2) Me 2 S (4 equiv.) 3) Conditions A R 2 1a: R 1 =H, R 2 =Ph 1b: R 1 =Me, R 2 =Ph 1c: R 1 =Me, R 2 =pF-Ph 1d: R 1 =pent-4-enyl, R 2 =Ph 1f: R 1 =Me, R 2 =CO 2 Et 1g: R 1 =nC 6 H 13 , R 2 =CO 2 Et Substituted furans 1a-d and 1f-g (2.5 mmol for 1a or 5.0 mmol for 1b-d and 1f-g) and rose Bengal (1 mol%, 25.4 mg in case of 1a or 50.8 mg in case of 1b-d and 1f-g) were dissolved in MeOH (total volume 5 mL, 0.5 M for 1a or 1.0 M for 1b-d and 1f-g).The resulting solution was transferred to the nebulizer via a liquid pump (flow rate set at 0.5 mL/min) and timing was initiated for calculation of the exact flow rate.The solution was dispersed by the nebulizer into the reaction cylinder irradiated by the LEDs (natural white light 3800 -4200 K, 10 W/m, 1050 Lm/m) using oxygen as the nebulizing gas (50 psi backpressure).When all the solution had been dispersed the exact flow rate was calculated and the three-way valve on the uptake line was switched to pure MeOH (2 mL) to flush out the system.The crude mixture was collected in the two cooled spherical flasks placed in series.A small sample of the crude mixture was concentrated in vacuo for the measurement of the conversions by 1 H NMR.Then, Me 2 S (4 equiv, 730 μL, 10 mmol in case of 1a or 1.46 mL, 20 mmol in case of 1b-d and 1f-g) was added and the solution was stirred for 1 h at rt.In many cases for the rapid reduction of hydroperoxide intermediates, the two cooled collection flasks were prefilled with excess of Me 2 S in MeOH (see below).When the reduction was completed, as indicated by tlc, Et 3 N (0.3 equiv, 105 μL, 0.75 mmol in case of 1a or 209 μL, 1.5 mmol in case of 1b-d and 1f-g) was added and the mixture was stirred for 0.5 -1 h at the same temperature.After completion of the reaction, a saturated aqueous solution of NH 4 Cl (20 mL) was added and the mixture was extracted with EtOAc (3× 20 mL).The combined organic layers were dried over MgSO 4 and concentrated in vacuo.The crude product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc) to afford the corresponding 4hydroxy-cyclopent-2-enones of type 2. For furan 1b the same protocol was applied on a larger scale (50 mmol) with very similar results.The two cooled collection flasks placed in series were prefilled with excess of Me 2 S in MeOH (3 equiv in the first flask and 1 equiv in the second flask), for the fast reduction of the initially formed hydroperoxides of type A and B (Scheme 1).-5-phenylcyclopent-2-enone (2a) 2,5 The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1a (395 mg, 2.5 mmol).Consumption of the 5 mL reaction solution took 8.45 min (actual flow rate = 0.59 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solution was stirred at rt for a further 1 h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 3:1).Yield 76% (330 mg).206.4, 163.1, 136.5, 133.1, 128.4 (2C), 127.9 (2C), 126.9, 78.0, 61.3 ppm.

4-Hydroxy
The relative configuration was assigned by comparing the reported NMR data from the literature 2,5 with our data.The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1b (860 mg, 5.0 mmol).Consumption of the 5 mL reaction solution took 9.20 min (actual flow rate = 0.54 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the solution stirred at rt for a further 1h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 4:1).Yield 70% (658 mg).5-(4-Fluorophenyl)-4-hydroxy-4-methylcyclopent-2-enone (2c) The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1c (950 mg, 5.0 mmol).Consumption of the 5 mL reaction solution took 8.95 min (actual flow rate = 0.56 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solution stirred at rt for a further 1h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 3:1).Yield 76% (784 mg).

4-Hydroxy-4-(pent-4-enyl)-5-phenylcyclopent-2-enone (2d)
The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1d (1.13 g, 5.0 mmol).Consumption of the 5 mL reaction solution took 9.83 min (actual flow rate = 0.51 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solutions stirred at rt for a further 1h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 8:1).Yield 67% (811 mg).Ethyl 2-hydroxy-2-methyl-5-oxocyclopent-3-enecarboxylate (2f) 2  The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1f (840 mg, 5.0 mmol).Consumption of the 5 mL reaction solution took 10.27 min (actual flow rate = 0.49 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solution stirred at rt for a further 0.5 h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 2:1).Yield 61% (561 mg).The diastereomeric ratio of the easily epimerizable product 2f was determined as being 5:1 in the crude reaction mixture and 2:1 after the chromatographic purification.
For this substrate (1f), the procedure was repeated a number of times using air as the nebulizing gas for different initial substrate concentrations (Table 2 in main text of paper).These latter experiments were conducted with the pyrex reaction chamber placed in a vertical position.Exact flow rates were between 0.55 -0.62 mL/min and isolated yields varied from 48 -69 % (see, Table 2).In all other aspects these procedures were identical to the one described above.Ethyl 2-hexyl-2-hydroxy-5-oxocyclopent-3-enecarboxylate (2g) The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1g (1.19 g, 5.0 mmol).Consumption of the 5 mL reaction solution took 10.90 min (actual flow rate = 0.46 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solution stirred at rt for a further 1h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 2:1).Yield 47% (597 mg).The diastereomeric ratio of the easily epimerizable product 2g was determined as being 3:1 in the crude reaction mixture and 13:1 after the chromatographic purification.

General procedure for the preparation of 4-methoxy-2-cyclopentenones of type 3
Substituted furans 1a-1g (2.5 mmol for 1a or 5.0 mmol for 1b-1g) and rose Bengal (1 mol%, 25.4 mg in case of 1a or 50.8 mg in case of 1b-1g) were dissolved in MeOH (total volume 5 mL, 0.5 M for 1a or 1.0 M for 1b-1g).The resulting solution was transferred to the nebulizer via a liquid pump (flow rate set at 0.5 mL/min) and timing was initiated for calculation of the exact flow rate.The solution was dispersed by the nebulizer into the reaction cylinder irradiated by the LEDs (natural white light 3800 -4200 K, 10 W/m, 1050 Lm/m) using oxygen as the nebulizing gas (50 psi backpressure).When all the solution had been dispersed the exact flow rate was calculated and the three-way valve on the uptake line was switched to pure MeOH (2 mL) to flush out the system.The flow rate was measured based on the time needed for the nebulization of 5 mL of photooxidation solution.The crude solution was collected in the two cooled spherical flasks placed in series.A small sample of the crude solution was concentrated in vacuo for the measurement of the conversion by 1 H NMR.Then, Me 2 S (4.0 equiv, 730 μL, 10 mmol in case of 1a or 1.46 mL, 20 mmol in case of 1b-1g) was added and the solution was stirred for 1 h at rt.In many cases for the rapid reduction of hydroperoxide intermediates, the two cooled collection flasks were prefilled with excess of Me 2 S in MeOH.When the reduction was completed, as indicated by tlc, Et 3 N (0.5 equiv, 348 μL, 2.5 mmol in case of 1b-1d and 1f, or 174 μL, 1.25 mmol in case of 1a or 1.0 equiv, 696 μL, 5.0 mmol in case of 1g) or NaOH (1.5 equiv, 300 mg, 7.5 mmol in case of 1e) was added and the solution was stirred for 1 -12 h at the same temperature.After the completion of the reaction, a saturated aqueous solution of NH 4 Cl (20 mL) was added and the mixture was extracted with EtOAc (3× 20 mL).The combined organic layers were dried over MgSO 4 and concentrated in vacuo.The crude product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc) to afford the corresponding 4methoxy-cyclopent-2-enones of type 3.The reaction was accomplished according to the general experimental procedure described above, utilizing furan 1a (395 mg, 2.5 mmol).Consumption of the 5 mL reaction solution took 9.15 min (actual flow rate = 0.55 mL/min).Then Me 2 S was added followed later, after completion of the reduction (as indicated by tlc), by Et 3 N and the resulting solution stirred at rt for further 12 h.The product was purified by flash column chromatography (silica gel, petroleum ether:EtOAc = 6:1).Yield 65% (306 mg).

Figure 4 .
Figure 4.The cone angle of the nebulizer.

Figure 7 .
Figure 7.The aerosol "cloud" formed after 30 sec of nebulization.For better viewing of the aerosol the LED strip lights have been omitted.